Notch signalling defines dorsal root ganglia neuroglial fate choice during early neural crest cell migration

Abstract

Background The dorsal root ganglia (DRG) are a critical component of the peripheral nervous system, and function to relay somatosensory information from the body’s periphery to sensory perception centres within the brain. The DRG are primarily comprised of two cell types, sensory neurons and glia, both of which are neural crest-derived. Notch signalling is known to play an essential role in defining the neuronal or glial fate of bipotent neural crest progenitors that migrate from the dorsal ridge of the neural tube to the sites of the DRG. However, the involvement of Notch ligands in this process and the timing at which neuronal versus glial fate is acquired has remained uncertain. Results We have used tissue specific knockout of the E3 ubiquitin ligase mindbomb1 (Mib1) to remove the function of all Notch ligands in neural crest cells. Wnt1 - Cre ; Mib1 fl / fl mice exhibit severe DRG defects, including a reduction in glial cells, and neuronal cell death later in development. By comparing formation of sensory neurons and glia with the expression and activation of Notch signalling in these mice, we define a critical period during embryonic development in which early migrating neural crest cells become biased toward neuronal and glial phenotypes. Conclusions We demonstrate active Notch signalling between neural crest progenitors as soon as trunk neural crest cells delaminate from the neural tube and during their early migration toward the site of the DRG. This data brings into question the timing of neuroglial fate specification in the DRG and suggest that it may occur much earlier than originally considered. Electronic supplementary material The online version of this article (10.1186/s12868-019-0501-0) contains supplementary material, which is available to authorized users.

Notch signaling is a critical initiator of roof plate formation as revealed by the use of RNA profiling of the dorsal neural tube

“…Although ISH of these markers prevented us from accurate quantification, a clear increase in the dI2 interneuron subset was apparent at both stages ( As also previously reported, we observed no effect on specification and emigration of AP2a+ NC cells at E9.5 in Wnt1-Cre; Mib1 fl/fl mutants when compared to wildtype [( Supplementary Fig. S9 A,B, and see [37] for quantification], suggesting that Notch signaling is involved in RP/interneuron development but not in early stages of NC ontogeny, as also seen in our quail experiments.…”

“…The copyright holder for this this version posted December 9, 2020. ; https://doi.org/10.1101/2020.12.09.417279 doi: bioRxiv preprint E11.5, as previously documented ( Supplementary Fig. S9 A-F) [37]. Likewise, we tested for cell proliferation of the Dll1-negative dorsal cell population by pulse labeling E10.5 wildtype and Wnt1-Cre; Mib1 fl/fl embryos with EdU.…”

“…In the present study, however, electroporation was performed following initial NC specification and no overt defects in subsequent migration were monitored. Nevertheless, at later stages, Notch was shown to play significant roles in neuron-glia fate decisions within NC-derived dorsal root ganglia [37,57]. preprint (which was not certified by peer review) is the author/funder.…”

“…3E,F,I,J). To inactivate Notch signaling in the dorsal NT, we conditionally removed the ubiquitin ligase Mindbomb1 (Mib1) that is required for the functional internalization of all Notch ligands, by intercrossing Mib1 fl/fland Wnt1-Cre mice[37]. As the Wnt1 promoter drives expression of Cre in the dorsal third of the NT prior to the NC stage, this cross abolishes Notch activity prior to and during RP formation.…”

Differentiation of Mesenchymal Stem Cells to Neuroglia: in the Context of Cell Signalling

“…Notch is a single spanning transmembrane protein that regulates the spatial patterning, timing and outcomes of many different cell fates during development (76). In embryos, notch signalling occurs by lateral inhibition, thereby a greater variation occur in the levels of transcriptional factors and their targets leading to suppression of neuronal differentiation (66).…”